The mammalian bombesin peptides gastrin releasing peptide (GRP) and neuromedin B (NMB) mediate a range of biological responses in normal cells, including promotion of paracrine or autocrine growth in some human small cell lung carcinoma (SCLC) cells. Recently we reported the cloning and characterization of two pharmacologically distinct rodent and human bombesin peptide receptors (gastrin-releasing peptide receptor (GRP-R) and neuromedin-B receptor (NMB-R)), with distinct patterns of expression in normal and malignant cells. Both receptors consist of seven putative membrane-spanning domains separated by short intracellular and extracellular loops, which are coupled to phospholipase C activation, inositol phosphate metabolism, and calcium mobilization through pertussis toxin insensitive G-proteins. GRP-R binds GRP at high affinity, while NMB-R binds NMB at high affinity. Construction and characterization of GRP-R/NMB-R chimeric receptors indicates that transmembrane domain 5 and the third intracellular loop are critical for high affinity binding of NMB by NMB-R. More precise functional definition of specific amino acids of importance in this domain is currently underway. In addition, a third mammalian bombesin receptor (BRS-3) has been cloned from NCI-N417, a human SCLC cell line. This receptor is activated by bombesin peptide ligands, but at higher concentrations than GRP-R or NMB-R, indicating that BRS-3 has lower affinity for GRP and NMB. BRS-3 shows a very limited pattern of expression in normal tissues, restricted to the secondary spermatocytes of testis. In contrast, many cultured human lung carcinoma express BRS-3 mRNA. The unique pharmacology and limited distribution of BRS 3 in normal tissues provide a rationale to search for a bombesin related compound that binds BRS-3 at high-affinity, which could potentially be used to target toxic compounds to the cell surface of human lung carcinoma cells.